Mucus is a thin film of protective viscoelastic liquid which lines the airways, gastrointestinal tract, and other organs containing mucus membranes. Mucus is an aqueous solution in which the major component is a glycoconjugate, known as mucin. Mucin secretion may be constitutive, regulated, or may occur in response to external stimuli, e.g., irritants.
In the lungs, improper or inappropriate mucus or mucin secretion, e.g., mucus hypersecretion, can result in severe medical conditions such as chronic bronchitis (CB), asthma, chronic obstructive pulmonary disease (COPD), and bronchiectasis. Patients suffering from cystic fibrosis (CF) will manifest pulmonary disorders associated with mucus hypersecretion, and may also have gastrointestinal complications.
Chloride channels, widely distributed throughout various tissues, play roles as diverse as maintaining membrane potential in muscles to movement of Cl− for fluid and electrolyte transport in epithelial tissues. Several studies have suggested that a calcium activated secretory pathway for Cl− may play a role in modulating the disease severity in various tissues of CF patients. (See, Anderson and Welsh (1991) Proc. Natl. Acad. Sci. 88:6003–6007; Knowles, et al. (1991) N. Engl. J. Med. 325:533–538; Mason, et al. (1991) Br. J. Pharmacol. 103:1649–1656; Wagner, et al. (1991) Nature 349:793–796; and Willumsen and Boucher (1989) Am. J. Physiol. 256(Cell Physiol. 25):C226–C235.)
A new family of proteins has recently been discovered that mediates a Ca2+-activated Cl− conductance in a variety of tissues. Members of this family that have been identified include: bovine lung endothelial cell adhesion molecule, Lu-ECAM-1 (Elble, et al. (1997) J. Biol. Chem. 272:27853–27861); bovine Ca2+-activated Cl−, CaCC or bCLCA1 (Cunningham, et al. (1995) J. Biol. Chem. 270:31016–31026); murine CLCA1, mCLCA1 (Gandhi, et al. (1998) J. Biol. Chem. 273:32096–32101); human CLCA1, hCLCA1 (Gruber, et al. (1998) Genomics 54:200–214); murine Gob-5, mGob-5 (Komiya, et al. (1999) Biochem. Biophys. Res. Comm. 255:347–351; and human CLCA2, hCLCA2 (Gruber, et al. (1999) Am. J. Physiol. 276(Cell Physiol. 45):C1261–C1270.) Recently, Holroyd, et al., PCT publication No. WO 99/44620, described mouse and human channels that are induced by IL-9. Collectively, these channels are referred to as Calcium-activated Chloride Channels (CLCA).
It has been reported that the stimulation of chloride secretion results in the secretion of mucin from goblet cells in the intestinal epithelium. (Halm, et al. (1995) Am. J. Physiol. 269:929–942.) The murine Gob-5 gene, mGob-5, has been shown, through in situ hybridization, to be expressed in the mucus-secreting cells of the stomach, small intestine, colon, and uterus, along with slight expression in the trachea. (Komiya, et al. supra.) Similarly it was suggested that human CLCA1, the human homolog of mGob-5, may also have a role in mucus secretion. See e.g., Nakanishi et al., Proc. Nat'l Acad. Sci. USA (Apr. 24, 2001) 98: 5175–5180.
To date, however, a definitive chloride channel target for regulating mucin secretion has yet to be identified, particularly with respect to mucin secretion by cells of the respiratory system. As such, there is a continued need for the identification of a specific chloride channel target that can be used to modulate mucin secretion by respiratory system cells.
Relevant Literature
Publications disclosing hCLCA2 include: WO 00/73438; WO99/47674; and WO99/44620; as well as Genbank accession nos. AX054697; Z24653; AF043977; AB026833; AF127980; AA726662. See also Nakanishi et al., Proc Natl Acad Sci USA 2001 Apr. 24;98(9):5175–80.